Marker Assisted Selection Against Genetic Defects in Livestock.
Intense selection for desired characteristics in livestock often results in increased inbreeding which contributes to the emergence of novel recessive defects. Examples of such outburst in Holstein-Friesian cattle include bovine leucocyte adhesion deficiency (BLAD)(1) and complex vertebral malformation (CVM)(2). Calf mortality resulting from such defects causes important economic losses and raises welfare concerns.
Most inherited defects are autosomal recessive, and are typically due to loss-of-function mutations (symbol “d”) in essential genes. Matings between animals that are healthy but carry one copy of the mutation (genotype “+/d”, i.e. “carriers”) will yield 25% of homozygous mutant animals (genotype “d/d”) that will be affected. A diagnostic test that allows the identification of +/d carrier animals, can be used either to cull carrier animals thereby eliminating the mutation and hence the defect from the population, or to avoid “at risk” matings between carrier sires and dams. The recent development of highly effective genomic tools, now allows for the rapid identification of the causative “d” mutations at the molecular level (3). Once identified, effective diagnostic tests can be developed using a range of generic DNA-based technologies that are well known by the people skilled in the art.
The Brachyspina Syndrome and Locus.
Recently (4) a new genetic defect, referred to as the brachyspina syndrome, was identified in Holstein-Friesian dairy cattle. Affected animals are characterized by severely reduced body weight, growth retardation, severe vertebral malformations associated with a significant shortening of the spine (brachyspina) and long and slender limbs. In addition, affected animals exhibit inferior brachygnatism as well as malformation of the inner organs, in particular the heart, kidneys and testis. All reported cases traced back on both sire and dam side to a common ancestor, suggesting autosomal recessive transmission.
We previously positioned the brachyspina locus in a 2.46 Mb genomic segment on bovine chromosome 21 (5) using recently developed 50K SNP arrays and a statistical approach called “autozygosity mapping” (3). Based on these findings, we developed an “indirect” diagnostic test on the basis of a panel of SNP markers spanning the brachyspina locus. Such an indirect test, often referred to as haplotype-based test, can and has already been used to detect +/d carrier animals. However, because the association between the disease causing “d” allele and the SNP alleles is not perfect, such indirect test suffer from a lack of senstivity and specificity. Some homozygous +/+ animals may erroneously be called carriers, while some +/d carrier animals may be missed. Improved diagnostic tests, ideally based on the detection of the causative mutation hence having near-perfect sensibility and specificity, are thus needed.
Effect of the Brachyspina Syndrome on Fertility.
We previously (5) reported that cows inseminated with sperm from sires that carry the brachyspina mutation show a decrease in non-return rate (the fact of not returning into heat as a result of successful pregnancy), an increase in stillbirth, and an increased culling rate. All these features are thought to result from embryonic and fetal mortality of ˜4% of conceptuses. In addition to causing the brachyspina syndrome, the brachyspina mutation or mutations thus has/have an important effect on male and female fertility, two of the most important economic traits in dairy cattle breeding. Being able to detect the brachyspina mutation(s) via an appropriate diagnostic test would thus have an important impact on improving fertility in Holstein-Friesian dairy cattle.